Phthalimido- and isoindolinyl-alkylpiperazines and their preparation



United States Patent 130- AND ISGINDOL-ALKYL- PIPERAZINES AND THEIRPREPARATIUN Bernard L. Zenitz, Colonie, and Lewis P. Albro, Greenbush,N.Y., assignors to Sterling Drug, Inc., New York, N.Y., a corporation ofDelaware No Drawing. Filed Nov. 2, 1962, Ser. No. 235,114

9 Claims. (Cl. 260-268) This invention relates to novel piperazinederivatives and to processes for preparing the same.

In particular, the invention relates to4-substituted-lphthalimidoalkylpiperazines and4-substituted-1-isoindolinyl-alkylpiperazines which have in their freebase form the general formula wherein R is a member of the groupconsisting of methyl and carbo-lower-alkoxy radicals, A is an alkyleneradical, and Y is a member of the group consisting of phthalimido andisoindolinyl, either of which can bear one to four substituents. Saidsubstituents are illustrated by, but not limited to halogen,lower-alkoxy, lower-alkyl, loweralkyl-mercapto, and the like.

In general Formula I above, R isrnethyl or carbolower-alkoxy.Carbo-lower-alkoxy radicals have the formula CO lower alkyl in which thelower-alkyl moiety is a monovalent straightor branched-chain saturatedhydrocarbon radical of from one to six carbon atoms. Representative ofcarbo-1ower-alkoxy radicals -are 'carbomethoxy, carboethoxy,carbopropoxy, carboisopropoxy, carbobutoxy, carbo-isobutoxy,carbo-tert.- butoxy, carbopentoxy, carbohexoxy, and the iike.

In Formula I above A is alkylene, that is, a straightor branched-chainsaturated divalent hydrocarbon radical having from two to ten carbonatoms in which the points of attachment to the remainder of the moleculeare on diiferent carbon atoms. In other words, the two nitrogen atomsjoined by the radical A are separated by at least two carbon atoms.Representative of alkylene radicals are and the like.

In Formula I above, Y is phthalimido or isoindolinyl, that is, a radicalcorresponding to the general formula wherein X represents respectivelyan oxygen atom (O),

. or two hydrogen atoms (H and Z represents from zero .Y is phthalimido,and when R is methyl, Y represents isoindolinyl.

The compounds of Formula I wherein R is carbo- "ice lower-alkoxy and Yis phthalirnido are prepared by causing a phthalimidoalkyl halide toreact with a l-carboloWer-alkoxy-piperazine. The process is preferablycarried out in an inert solvent in a preferred temperature range betweenabout 50 C. and about 150 C. It is convenient to employ an inert solventwhich boils within the above preferred temperature range and to carryout the reaction at the reflux temperature of the solvent.Representative of suitable solvents for this purpose are benzene,toluene, chloroform, carbon tetrachloride, and lower-aliphatic alcohols.

Optionally, a proton acceptor can be added to the reaction mixture. Byproton acceptor is meant a substance capable of reacting with the acidproduced by the reaction of the phthalimidoalkyl halide andcarbo-loweralkoxypiperazine. In the absence of an additional protonacceptor, the basic nitrogen of the piperazine moiety reacts with thehydrogen halide produced in the reaction to give the hydrohalide saltform of the product.

The phthalimidoalkyl halides used as intermediates are prepared byconventional procedures. For example, they can be prepared by thereaction of the potassium salt of the desired phthalimide with anequivalent of alkylene dihalide, for example, alkylene dibromide,alkylene dichloride, or alkylene chlorobromide. The phthalimidoalkylhalides can also be prepared by the reaction of a monohaloalkanol with apotassium phthalimide followed by reaction of the resultinghydroxyalkylphthalimide with a halogenating agent, for example, thionylchloride, hydrogen bromide, hydrogen iodide, phosphorous trichloride,and the like.

In the form of their free bases, the 1-carbo-loweralkoxy 4phthalimidoalkylpiperazines so produced are white crystalline solidswhich are slightly soluble in water. They are basic substances, havingone basic nitrogen atom, and thus form acid-addition andquaternaryammonium salts wtih strong acids and esters of strong acidsrespectively. The acid-addition salt forms are the full equivalents oftheir corresponding free bases in respect to their physiologicalactivity.

The compounds of Formula I above wherein R is methyl and Y isisoindolinyl are prepared by causing compounds of Formula I wherein R isa carbo-loweralkoxy group and Y is phthalimido to react with a suitablereducing agent, for example, lithium aluminum hydride. The process iscarried out by mixing thel-carbolower-alkoxy-4-phthalimidoalkylpiperazine with an excess oflithium aluminum hydride in a suitable inert solvent at a temperaturebetween about 20 C. and about C. Representative of suitable inertsolvents for this reaction are di-lower-alkyl others, for example,diethyl ether, aryllower-alkyl ethers, for example, anisole, andtetrahydrofuran.

The 1-methyl-4-isoindolinyl-alkylpiperazines so produced are basicsubstances, having three basic nitrogen atoms, and form mono-, diandtri-basic acid-addition salts and quaternary ammonium salts uponreaction with strong acids and esters of strong acids respectively. The

acid-addition salts are the full equivalents of their corresponding freebases in respect to their physiological properties.

The acid-addition salt forms of the compounds of the invention areprepared by causing the corresponding free bases to react with the usualstrong organic or inorganic acids employed for this purpose, usually inan inert solvent. Examples of such strong acids include hydrochloric,hydrobromic, sulfuric, phosphoric, citric, tartaric, quinic, benzenesulfonic, methanesulfonic acid, and the like. i

As another aspect of the invention, the compounds of Formula I wherein Xis oxygen and R is a carbo-loweras alkoxy group can be used asintermediates for preparing quaternary ammonium salts having the formulawherein R is lower-alkyl, A is lower-alkylene, R" is a member of thegroup consisting of lower-alkyl, loweralkenyl andmonocyclic-aryl-lower-alkyl, and Z is an qion.

In Formula 111, the aklylene group A, and the loweralkyl group R, are asdefined above in formula I.

The group R can be lower-alkyl, and, as such, is as defined above forlower-alkyl.

The group R" can be lower-alkenyl, and as such, is a straight-orbranching-chain hydrocarbon radical containing from two to six carbonatoms and containing at least one double bond. The lower alkylene groupis illustrated by, but not limited to viny, allyl, propenyl, 2-butenyl,2,4-pentadienyl, and 3-hexenyl.

The group R can be monocyclic-aryl-lower-alkyl, and as such, is amonocarbocyclicor monoheterocyclic-aryl radical bonded through adivalent, saturated, straightor branched-chain aliphatic radicalcontaining from one to six carbon atoms. Thus, themonocyclic-aryl-lower-alkyl group is illustrated by, but not limited tobenzyl and benzyl substituted by from one to three inert substituents of'low molecular weight, furyl, thenyl, picolinyl, and furyl,

thenyl, and picolinyl substituted by from one to three inertsubstitutents of low molecular weight, penyl-ethyl, phenylpropyl,phenylbutyl, phenylamyl, and phenylhexyl, and phenylethyl, phenylpropyl,phenylbutyl, phenylamyl, and phenylhexyl substituted by from one tothree substituents of low molecular weight. Exemplary of saidsubstituents are halogen, nitro, lower-alkoxy, lower-alkyl,trifluoromethyl, and the like.

The anion, Z, is an inorganic, negatively-charged ion, for example,halide, sulfate, acid sulfate, nitrate, and the like or an organicsulfonate ion, for example, methanesulfate, benzenesulfonate,p-toluenesulfonate, p-chlorobenzenesulfcnate, and the like.

The quaternary ammonium salts of Formula III are prepared by causing thecorresponding free bases to react with esters of strong inorganic ororganic sulfonic acids, for example, lower-alkyl halides, lower-alkylarenesulfonates, and lower-alkyl alkanesulfonates. The reaction of thefree base and the quarternizing agent takes place upon simple admixtureof the components, preferably in the presence of an inert solvent,although heating may be applied to accelerate the reaction.

The acid-addition salt forms and the quaternary compounds preferablyhave anions which are physiologically acceptable, that is, the anions donot appreciably increase the toxicity of the compound as a whole towardanimal organisms. Such anions include, for example, the chloride,bromide, iodide, sulfate, acid sulfate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-chlorobenzenesulfonate, and thelike. Salt forms having toxic anions are, however, useful in that theyserve as characterizing derivatives of the free bases and serve asintermediates for preparing non-toxic quarternary salt forms byconventional ion-exchange reactions. All acid-addition salt forms,regardless of the nature of their associated anions, are useful asintermediates in the purification of the free bases.

Pharmacological evaluation of the compounds has shown that they possesshypotensive and anti-spasmodic activity when administered to animalorganisms in nontoxic doses. The new compounds are thus useful forlowering blood pressure in certain hypertensive conditions Example 1.1-carbeth0xy-4 [Z-(Z-phthalimido) ethyl] pi perazz'ne [Formula I, X==O,n=2, R=COOEt1 A mixture containing 21.3 g. (0.135 mole)1-carbethoxypiperazine and 16.0 g. (0.065 mole) ofN-(2-bromoethyl)-phtl1alirnide in 100 ml. of dry toluene was refluxedfor twenty-four hours. The precipitate of l-carbethoxypiperazinehydrobromide was filtered off, and the filtrate was concentrated underreduced pressure, whereupon it crystallized. Recrystallization frompercent aqueous ethanol and then from methanol gave pure l-carbethoxy-4-[2-(2-phthalimido)ethyl]piperazine consisting of white ganularcrystals melting at 105.8l07.4- C. (corr.).

Example 2.1-carbeth0xy-4-[2-(2-phthalimid0)ethyl] piperazine4-methi0dide was prepared from the free base of Example 4 by refiexing0.01 mole of the latter compound with 0.02 mole of methyl iodide in 50ml. of methyl ethyl ketone for about five hours. After recrystallizationfrom absolute ethanol, the1-carbetl1oxy-4-[2-(2-phthalimido)ethyl]piperazine, consisting of fine,pale-yellow crystals, melted at 222.6-2252 C. (corr.).

Example 3.1-methyl-4-[2-(2-is0ind0linyl) ethyl] piperazinetrihydrochloride [Formula I, X=H R=CH n=2] To a suspension of 15.2 g.(0.4 mole) of lithium aluminum hydride in 500 ml. of absolute ether wasadded a solution containing 34.5 g. (0.104 mole) of l-carbethoxy-4-[2-(2-phthalimido) -ethyl]piperazine in 900 ml. of absolute ether at arate sufficient to maintain the reaction mixture at reflux withoutexternal heating. After the addition was complete the mixture wasrefluxed for about four hours and allowed to cool. Water was then addeddropwise to hydrolyze the resulting aluminum complex. The precipitatewhich formed was repeatedly washed with ether and the solvent wasremoved from the ether solution. The remaining brown oil, consisting ofcrude 1- methyl-4-[2-(2-isoindolinyl)-ethyl]piperazine, was crystallizedfrom n-pentane. After recrystallization from acetone, the product freebase melted at 68-72". The trihyd'rochloride salt was prepared by addingan excess of ethereal hydrogen chloride to an ethanolic solution of thefree base. After repeated recrystallization from aqueous ethanol, thepure 1-methyl-4-[2-(2-isoindolinyl)ethyl] piperazine trihydrochloridemelted at 287290 C. (corr.).

The following compounds were prepared according to the procedure givenin Example I from l-carbethoxypiperazine and the designatedphthalimidoalkyl halide:

Example 4. 1-carbeth0xy-4-[5-(2-phthalimido)pentyIJ-piperazz'rzehydrochloride, M.P. 201.0-204.8 C. (corr.), fromN-(5-chloropentyl)phthalimide;

Example 5.] carbeth0xy-4-[3-(2-phthalimido)pr0- pyZJ-piperazine, M.P.95.0-96.6 C. (corr.), from N- (3-chloropropyl) piperazine;

Example 6.1-carbethoxy-4-[4-(2-phthalimido)butyl] piperazine, M.P.71.873.2 C. (corr.), from N-(4-chlorobutyl pip erazine.

The following compounds were prepared according to the procedure givenin Example II from methyl iodide and the appropriate free base:

Example 7.-1 -carbethoxy-4-[3-(2-phthalimid0)propyl]-p)iperazine4-methi0dide, M.P. 209.82l2.6 C.

corr.

Example 8.] 7 carbethxy-4-[5-(2-phthalimid0)pentyl]-piperazine4-methi0dide, M.P. 150.4l52.4 C. (corn).

The following compounds were prepared according to the procedure givenin Example III by reducing the appropriate 1 carbethoxy 4(phthalimidoalkyl)piperazine:

Example 9.1- methyl-4-[3-(2 isoindolinyl) pr0pyl1- piperazz'netrz'hydrochloride, M.P. 269.627l.6 C. (corn);

Example 10. 1 methyl-4-[4-(2-is0indolinyl) butyllpiperazine, M.P.68.6-71.8 C. (corn);

Example 11. 1 -methyl-4-[5-(2-isoindolinyl)pentyl]- piperazinetrihydroclz'loride, M.P. 279.028l.4 C. (corn),

The following additional examples of the invention can be. preparedaccording to the procedure shown in Example Example 12.lcarbethoxy-4[3-(4,5,6,7-tetrachl0ro-2-phthalimid0)-2-methylpr0py'l]piperazine from 2 (3- chloro-Zmethylpropyl)-4,5,6,7 tetrachlorophthalimide and N-carbethoxypiperazine;

Example 13. 1 carbopropoxy -4-[8-(5-meth0xy2-phthalimido)-octyl]piperazine from 2-(8-chloro-octy1)-S-methoxyphthalimide and N-carbopropoxypiperazine;

Example 14.1-carb0but0xy-4-[9-(S-inethyl-Z-phthalimid0)-n0nyl]piperazine from 2-(9-chlorononyD-5-methylphthalirnide andN-carbobutoxypiperazine;

Example 15. 1 carbohexoxy -4 [6-(5-methoxy-2-phthalimido)-hexyl]-piperazine from 2-(6-chlorohexyl)-S-methoxyphth'alimide and N-carbohexoxypiperazine;

Example 16. l carbopentoxy -4-[2-,(4-n-butoxy-2-phthalimido)-pr0pyl]piperazine from 2-(2-chloropr0pyl)-4n-butoxyphthalimide and N-carbopentoxypiperazine;

Example 17. 1 carb0z's0pr0p0xy-4-[10-(4-methyl-2-phthalimido)-decyl]piperazine from 2 (l0-chlorodecyl)-4-methylphthalimide and N-carboisopropoxypiperazine;

Example 18. 1carb0is0but0xy-4-[7-(5-methylmercapto-Z-phthalimido)hepiyflpiperazinefrom 2-(7-chloroheptyl)--methylmercaptophthalimide andN-carboisobutoxypiperazine;

Example 19.-1-carb0-sec.but0xy-4-[4-br0m0-2-phthalimido)-2-ethylbutyl]piperazine from2-(4-chloro-2-ethylbutyl)-4-bromophthalimide andN-carbo-sec.-butoxypiperazine; and

Example 20. 1-carb0-tert.-bat0xy-4-[3-(5-chl0r0-2-phtlzalimido)-2-batyl]piperazine from 2 (3 -chloro-2-butyl)-5-chlorophthalimide and N-carbo-tert.-butoxypiperazine. Thelatter intermediate is prepared from piperazine and tert.-butylchloroformate.

The following examples can be prepared according to the procedure shownin Example 2:

Example 21 1-carbeth0xy-4- [3-(4,5,6,7-tetrachl0r0- Z-phthalz'mido)Z-methylpropyl]piperazine ethobromide, which has the formulaN-cHT-oH-orn-rf N o0oc,11, 01 cm Br can be prepared from1-carbethoxy-4-[3-(4,5,6,7-tetrachloro 2phthalimido)-2-methylpropyl]piperazine and ethyl chloride;

Example 22. 1-carbopropoxy-4-[8-(5-methoxy-2-phthalimido)-0ctyl]piperazine allylbromide, which has the formula can beprepared from l carbopropoxyl-[S-(S-methoxy-2-phthalimido)-octyl]piperazine and allyl bromide;

6 Example 23.]carbobutoxy-4-[9-(S-methyl-Z-phthalimid0)-n0nyl]piperazineelhomethanesulfonate, which has the formula which can be prepared fromequimolar quantities of 1- carbobutoxy 4 '[9(5-methyl-2-phthalimido)nonyl] piperazine and ethyl methanesulfonate;

Example 24.1 carbohexoxy 4 [6-(5-meth0xy-2- phthalimido)hexyl1-piperazine etha-p-chlorobenzenesulfonate, which has the formulacan be prepared from l-carbohexoxy-4-[6-(5-methoxy-2-phthalimido)hexyl]piperazine and ethyl pchlorobenzenesulfonate;

Example 25.] carbopentoxy 4 [2-(4-n-bat0xy-2-phthalimido)-pr0pyl]piperazine benzochloride, which has the formula .canbe prepared from 1-carbopentoxy-4-[2 (4-n-butoxy-2-phthalimido)-propyl]piperazine and benzyl chloride;

Example 2 6. 1 -carb0is0pr0p0xy-4- [1 0- (4 -me=thyl-2-phthalimido)-decyl]piperazine thenylchloride, which has the formula 0 l1 I L i011: H) N N COOCH(CH) can be prepared from equimolar quantitiesof l-carboisoprop oxy- 4- lO- (4-methyl-2-phthalimido) decyl] piperazineand thenyl chloride;

Example 27. 1-car'Jois0but0xy-4-[7-(5-methylmercapto 2phthalimido)heptyl]piperazine butobromz'a e which has the formula cmsfN-(CHah-N rr-oooonr-omom Br 6H, emu/ can be prepared from1-carbo-tert.-butoxy-4-[3-(5-ch1oro- 2-phthalimido)-2-butyl]piperazineand dimethyl sulfate; and

Example 29-] carbo-sec. but0xy-4-[4-(4-br0mo-2- phthalimido) 2ethylbutyl]piperazine ethobenbenesub fonate which has the formula can beprepared from l-carbo-seo-butoxy-4-[4-(4-bromo- Z-phthalirnido)-2-ethylbutyl] piperazine and ethyl benzenesulfonate.

The following 1-methyl-4-isoindolinylakylpiperazines can be preparedfrom the corresponding phthalirnides by reduction according to theprocedure shown in Example 3:

Example 30. 1 -methyl-4-[3-(4,5,6,7-tetrachlor0-2- isoindoli nyl-2-metlzylpro ply] pi perazine.

Example 31.] methyl 4 [8-(5-meth0xy-2-is0indolinyl) -0ctyl] piperazine;

Example 32.1-methyl-4-[9-(5-metlzyl-2-is0ind0linyl)- nonyl] piperazine;

We claimz' 1. 1 carbo-lower-alkoxy-4-[ (2-phthalimido)A]piperazine,wherein A is alkylene of from two to ten carbon atoms.

2. 1-carbethoxy-4-[S- Z-phthalirnido pentyl] piperazine.

3. 1-carbethoxy-4-[4-(Z-phthalimido)butyl1piperazine.

4. 1 carbethoxy 4-[3-(2-phthalirnido)propyl1piperazine.

5. 1-carbethoxy-4- [Z- hthalimido ethyl] piperazine.

6. 1 carbethoxy-4-[ (Z-phthalimido)A]-4-R-piperazinium salts withnon-toxic anions wherein R is selected from the group consisting oflower -alkyl, lower-alkenyl, and monocarbocyclic-aryl-lower-alkyl,wherein A is alkylene of from two to ten carbon atoms.

7. 1 carbethoXy-4-[2-(2-phthalimido)ethyl]piperazine 4-methio'dide. v

8. 1-carbethoxy-4- [3 Z-phthalimido propyl] piperazine 4-methiodide.

9. 1-carbethoxy-4- [5- (Z-phthalimido pentyl] piperazine 4-rnethiodide.

References Cited by the Examiner UNITED STATES PATENTS 2,672,460 3/54Conroy 260268 2,909,523 10/59 Bach et al 260268 3,055,901 9/62 Speranzaet al. 260-268 3,084,167 4/63 Rice 260-268 OTHER REFERENCES Fieser etal., Advanced Organic Chemistry, page 279, Reinhold Pub. Corp., New York'(1961).

Kermack et al., Journal Chemical Society (London), pp. 3096-3104 (1931).

Rice et al., Journal Organic Chemistry, vol. 19, pp. 884 893 (1954).

NICHOLAS S. RIZZO, Primary Examiner.

IRVING MARCUS, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,198,798 August 3, 1965 Bernard L. Zenitz et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 5, lines 41 and 42, for "-butoxy-4-[4-bromo-2- phthalimido", initalics, read butoxy-4[4-(4-bromo2 phthalimido in italics; column 6,lines 70 to 75, for that portion of the formula reading "SO CH read SOCH column lines 7 to 13, for that portion of' the formula reading-COOCH-C H -COOCH-C H I read I CH CH :olumn 8, line 9, for "-4-[Z-phthalimido" read -4-[2-(Z- :hthalimido Signed and sealed this 18thday of October 1966 SEAL) ttest:

NEST W. SWIDER EDWARD J. BRENNER :testing Officer Commissioner ofPatents

1. 1-CARBO-LOWER-ALKOXYL-4-((2-PHTHALIMIEO)A)PIPERAZINE, WHEREIN A IS ALKYLENE OF FROM TWO TO TEN CARBON ATOMS. 